In this grant the applicants will focus on a novel and key mechanism for the regulation of penile smooth muscle contractility, the nitric oxide (NO) pathway. The goals are to define the role of NO in penile erection, to study its physiologic regulation in the penis and to define how disease states interfere with the NO pathway. The following specific aims are proposed: I) to characterize nonadrenergic, noncholinergic (NANC) neurotransmission in corpus cavernosum; II) to characterize nitric oxide synthase (NOS) expression and activity in corpus cavernosum; III) to determine if NO regulates endothelin synthesis in the penis; and IV) to determine if NO directly interacts with sodium-potassium ATPase to regulate the contractility of corpus cavernosum smooth muscle (and . if sodium- potassium ATPase is involved in digoxin-associated impotence); and V) to determine if systemic diseases (i.e., diabetes mellitus) interfere with synthesis and/or availability of NO and alter endothelium- and NANC-mediated responses resulting in impotence.